The broad objective of this research is lung cancer prevention through elaboration of mechanisms in respiratory carcinogenesis and validation of biologic markers as predictors of lung cancer risk. Specifically, the predictive value of a panel of complementary biologic markers (carcinogen- DNA adducts, carcinogen-protein adducts, activated oncogenes, tumor suppressor genes, plasma vitamins and glutathione transferase activity) will be determined by assaying blood samples selected from 14,916 "enrollment" or baseline samples stored between 1982 and 1984 at the outset of a large-scale prospective cohort study (the Physician's Health Study of PHS). Over the 13 years of follow-up (1982-1995), blood samples from an estimated 92 cases and 184 matched controls will be available. In addition, tumor tissue will be obtained from all cases for biomarker analyses. Prior cross-sectional and case-control studies have suggested a link between the specified biomarkers and both exposure to environmental carcinogens and cancer risk. However, to date there have been no prospective or nested case-control studies that have attempted to determine the ability of these biologic markers, present prior to a clinical diagnosis, to predict individual risk of cancer. The parent study, the PHS, has already collected detailed smoking, environmental, health and dietary histories on each subject, and will also provide data on enrollment (baseline) plasma levels of vitamins (retinol, beta carotene and vitamin E). The combined laboratory measurements provide an opportunity to examine the possible mechanism by which vitamins and the genetically determined activity of the mu isoenzyme of glutathione-S-transferase (GST) may modify levels or presence of adducts, oncogenes and tumor suppressor genes (TSG), and hence alter cancer risk. This research thus fills important gaps in knowledge regarding prevention of lung cancer.